A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice

PLoS One. 2015 Jan 24;10(1):e0115709. doi: 10.1371/journal.pone.0115709. eCollection 2015.

Abstract

Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Allografts / drug effects
  • Allografts / pathology*
  • Animals
  • Female
  • Kidney Transplantation / adverse effects*
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Kidney Tubules / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Regeneration
  • Reperfusion Injury / drug therapy*
  • Transplantation, Homologous

Substances

  • Oligopeptides
  • alanyl-glutaminyl-glycyl-valine

Grant support

Studies were outsourced by, funded by, and designed in guidance with Exponential Biotherapies Inc. The funders, through GW, had a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript.